tbuckley/cabot-search huggingface dataset:
The cephalic phase of insulin release is modulated by IL-1β
Authors: Sophia J. Wiedemann, Kelly Trimigliozzi, Erez Dror, Daniel T. Meier, Jose Alberto Molina-Tijeras, Leila Rachid, Christelle Le Foll, Christophe Magnan, Friederike Schulze, Marc Stawiski, Stéphanie P. Häuselmann, Hélène Méreau, Marianne Böni-Schnetzler, Marc Y. Donath
Journal: Cell Metabolism (2022)

The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic β cells. Recently, IL-1β was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1β involves neuronal transmission. Furthermore, we found that cephalic phase insulin release was mediated by IL-1β originating from microglia. Moreover, IL-1β activated the vagus nerve to induce insulin secretion and regulated the activity of the hypothalamus in response to cephalic stimulation. Notably, cephalic phase insulin release was impaired in obesity, in both mice and humans, and in mice, this was due to dysregulated IL-1β signaling. Our findings attribute a regulatory role to IL-1β in the integration of nutrient-derived sensory information, subsequent neuronally mediated insulin secretion, and the dysregulation of autonomic cephalic phase responses in obesity.
P589: AGE AND AGE-ADAPTED RISK FACTORS HIGHLY INFLUENCE SURVIVAL PROBABILITY IN AML PATIENTS – A RETROSPECTIVE ANALYSIS
Authors: K. Nachtkamp, C. Zahner, A. Fricke, T. Ulrych, F. I. Schulz, A. Kündgen, P. S. Jäger, G. Kobbe, U. Germing
Journal: HemaSphere (2022)

Background: Advanced age is strongly associated with inferior overall survival in patients with acute myeloid leukemia (AML). Despite advances in modified treatment regimen and genetic analyses of underlying mutations the prognosis for patients above the age of 65 remains poor. Aims: The aim was to determine patient-related risk factors and disease-associated variables. Methods: 915 AML patients (498 < 65 years, 417 ≥ 65 years) treated at the University Hospital of Düsseldorf were analyzed. Patients were diagnosed between 2008 and 2020 comprising 484 males and 431 females. Median age was 63 years. Patients’ survival was calculated using Kaplan-Meier-plots and multivariate regression analyses were performed to identify prognostic factors for survival. Results: Age itself proved to be an independent risk factor for survival: 6.9 months within the group of patients ≥ 65 years, 166 months in patients < 65 years (p < 0.001). In patients ≥ 65 years aberrant cytogenetic findings and an inferior ECOG status were more frequent at the time of diagnosis. Comparison of survival within the same cytogenetic risk group yielded significant differences between the two age-stratified cohorts: Bearing cytogenetic aberrations associated with a favorable prognosis in the group with patients aged over 65 was associated with a median survival of 18 months whereas patients younger than 65 did not reach estimated median survival time (p < 0.001). When comparing patients with the same ECOG-status, advanced age was the most decisive prognostic factor for survival. This was highly significant in patients with ECOG status 0. In the group with higher ECOG status an influence of age was notable but of lower significance. In patients with pathologic lung function tests age turned out to be significant for survival: 26 months (≥ 65 years) vs. not reached (< 65 years) (p = 0.008). In patients with pathologic cardiac ultrasound findings results were similar with 26 months (≥ 65 years) vs. not reached (< 65 years) (p = 0.001). Whether AML was de novo or secondary affected survival probability only in the group aged below 65 (166 months de novo AML, 69 months secondary AML). Summary/Conclusion: Age has significant influence on patient- and leukemia-related factors, thus modulating the impact of other parameters on the prognosis. We were able to confirm the following independent negative predictive parameters on survival in AML patients: increasing age ≥ 65 years, high-risk genetic aberrations, comorbidities (lung, heart) and higher ECOG-status.
P662: PATIENT-REPORTED OUTCOMES FROM A PHASE 3 RANDOMIZED STUDY OF ZANUBRUTINIB VERSUS BENDAMUSTINE PLUS RITUXIMAB (BR) IN PATIENTS WITH TREATMENT-NAÏVE (TN) CLL/SLL
Authors: P. Ghia, G. Barnes, K. Yang, C. Tam, P. Hillmen, T. Robak, J. Brown, B. Kahl, T. Tian, A. Szeto, J. Paik, M. Shadman
Journal: HemaSphere (2022)

Background: Zanubrutinib is an oral, highly selective, next-generation Bruton tyrosine kinase (BTK) inhibitor. In cohort 1 of the phase 3 SEQUOIA trial (BGB-3111-304; NCT03336333), efficacy and safety of zanubrutinib and BR were compared in adult patients (pts) with TN chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). Aims: Here, we report the health-related quality of life (HRQoL) outcomes from an interim analysis of the SEQUOIA trial. Methods: Patient-reported outcomes (PROs) were secondary endpoints and assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS. Patients completed these questionnaires at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease progression, death, or withdrawal from study. The PRO endpoints included global health status (GHS), physical and role functions, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting, measured by QLQ-C30, with critical clinical cycles of Weeks 12 and 24. Descriptive analyses were performed on all questionnaire responses, and a mixed model for repeated measures was performed on the PRO endpoints at Weeks 12 and 24. Results: Baseline demographics and disease characteristics between the zanubrutinib (n=241) and BR (n=238) arms were similar. Across all pts, adjusted completion rates for PROs (# of pts who completed the questionnaire at each cycle divided by # of pts expected to complete the questionnaires) were high (~80%) at Weeks 12 and 24. Compared with pts who received BR, pts treated with zanubrutinib experienced greater improvements in HRQoL at Weeks 12 and 24 as reported on the QLQ-C30 (Table). By Week 24, significant improvements were observed with zanubrutinib vs BR in GHS, physical functioning, role functioning as well as greater reductions in diarrhea, fatigue, and nausea/vomiting. Per EQ-5D-5L VAS, comparable improvements from baseline between zanubrutinib and BR in the health status were observed at Weeks 12 (4.3 vs 3.5) and 24 (4.5 vs 4.9), respectively. Image:Summary/Conclusion: In the SEQUOIA trial, zanubrutinib was associated with significant improvements in HRQoL in pts with TN CLL/SLL without del(17p), as indicated by the PRO endpoints of the GHS, physical and role functions, and greater reductions in symptoms of fatigue, diarrhea and nausea/vomiting compared with BR.
P402: MUTATIONS IN BONA FIDE ONCOGENES KRAS AND DNMT3A ARE NOT RELATED TO DEPENDENCY IN ESTABLISHED TUMORS, IN PDX MODELS OF ACUTE LEUKEMIA IN VIVO
Authors: Y. Gao, M. Ghalandary, M. Becker, D. Amend, M. Rothenberg-Thurley, K. Metzeler, I. Jeremias
Journal: HemaSphere (2022)

Background: The role of oncogenic mutations during the process of tumor formation was intensively studied in genetically engineered mouse models, while much less is known about their function in established tumors of patients. Aims: To bridge the gap, we studied frequently mutated genes for their dependency in established tumors in vivo, using genetic engineering in patient-derived xenograft (PDX) models. Methods: Primary tumor cells from seven patients with acute myeloid leukemia (AML) were transplanted into immunocompromised NSG mice. PDX cells were lentivirally transduced to express the Cas9 protein and a sgRNA. The customized sgRNA library was designed and cloned using our CLUE platform (www.crispr-clue.de; Becker et al., Nucleic Acids Res. 2020). PDX cells transgenic for Cas9 and the CRISPR/Cas9 sgRNA library were transplanted into NSG mice, grown until advanced AML disease and sgRNA distribution measured by next-generation sequencing. From dropout hits in PDX in vivo screens, single molecules were validated by fluorochrome-guided competitive in vivo experiments, comparing cells with and without knockout in the same mouse and determining cell distributions by flow cytometry gating on the different recombinant fluorochromes. Human AML cell lines were studied in vitro for comparison. Results: We cloned a small customized sgRNA library targeting 34 genes recurrently mutated in AML and tested the library in two PDX AML models in vivo. In hit validation experiments, knockout of NPM1 abrogated in vivo growth in all PDX AML models tested, reproducing the known common essential function of NPM1. KRAS proved an essential function in PDX AML models both with and without an oncogenic mutation in KRAS, suggesting that patients suffering tumors both with and without KRAS mutation might benefit from treatment inhibiting KRAS. DNMT3A belongs to the genes most frequently mutated in AML, but most AML cell lines tested in vitro did not depend on DNMT3A and knockout of DNMT3A did not reduce, but rather increased AML cell line growth in vitro. In contrast, in PDX models in vivo, we found a clear essential function for DNMT3A in certain AML samples and PDX in vivo results were discordant to cell line in vitro data. These data highlight the complementary use of PDX models to study gene dependencies. To our surprise, the dependency of AML cells on DNMT3A was unrelated to the presence or absence of a hot spot mutation in DNMT3A. Summary/Conclusion: We conclude that both KRAS and DNMT3A harbor an essential function in certain patients established AML tumors in vivo, although independently from the presence of absence of a mutation in the gene. Warranting verification in additional patient samples, oncogenes and tumor entities, our data might indicate re-consider basic principles of decision making in Molecular Tumor Boards.
P952: THE ROLE OF AGE IN THE LONG-TERM TREATMENT OF MULTIPLE MYELOMA - A LONGITUDINAL ANALYSIS OF REGULAR CARE DATA
Authors: H. T. Steinmetz, M. Heinz, U. Totzke
Journal: HemaSphere (2022)

Background: Recently, we demonstrated in a longitudinal approach that the percentage of multiple myeloma (MM) patients reaching consecutive treatment lines in regular care is much higher than presumed, i.e. 88%, 66%, 44%, and 30% in 2nd, 3rd, 4th, and 5th line, respectively (Oncol Res Treat 44, 662-71). Aims: As the annual risk of death generally increases with age, we investigated here the impact of age on the course of MM treatment. Methods: MM patients treated in our outpatient clinic in Germany over 8 years were assigned to three groups of equal size according to age at diagnosis. Resulting subgroups were analyzed regarding their outcome and the probabilities of reaching consecutive therapy lines using a linear statistical model, as previously described for the analysis of the whole cohort. Results: Age groups were <65, 65-74, and ≥75 years. As compared to the two remaining groups, the proportion of male patients and of those with ISS 1 was considerably higher in the youngest age group while the median observation time was on average 7 months shorter in the oldest age group (Tab.). - Age <65 years Age 65-74 years Age ≥75 years Patientsb 50 (34.5%) 46 (31.7%) 49 (33.8%) womenb 18 (36.0%) 25 (54.3%) 23 (46.9%) Time observed [month]a 40.5 (0-198) 40 (2-152) 33 (0-197) - Stage at diagnosisb ISS R-ISS ISS R-ISS ISS R-ISS I 19 (38%) 11 (22%) 6 (13%) 9 (20%) 10 (20%) 3 (6%) II 11 (22%) 13 (26%) 21 (46%) 17 (37%) 17 (35%) 16 (33%) III 11 (22%) 6 (12%) 13 (28%) 2 (4%) 16 (33%) 6 (12%) Unknown 9 (18%) 20 (40%) 6 (13%) 18 (39%) 6 (12%) 24 (49%) Deathb 12 (24.0%) 8 (17.4%) 27 (55.1%) Cause of deathb MM 3 (25.0%) 1 (12.5%) 10 (37.0%) Other 5 (41.7%) 6 (75.0%) 13 (48.1%) Unknown 4 (33.3%) 1 (12.5%) 4 (14.8%) a median (range); b N (%) The probability of reaching consecutive treatment lines decreased in all age groups, but most strikingly in that of the oldest patients (Fig.). Age does not appear to play a major role for reaching subsequent lines at ages up to 75 years though. Up to this age, patients were thus even more likely to reach subsequent lines than previously shown for the total cohort, increasing to about a 50% chance for the 5th line of therapy. The mean age at death was 83 (SD 4.8) years in the oldest age group, but in none of the age groups, the leading cause of death was MM. Image:Summary/Conclusion: Only age beyond 75 years at baseline significantly reduces the probability of reaching 2nd or higher lines of MM therapy.
P588: IMPROVED OUTCOME OF RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA BY ADDITION OF LIPOSOMAL ADRIAMYCIN TO CLAG CHEMOTHERAPY
Authors: H. Yao, C. Zhang, J. Li, X. Yin, J. Rao, X. Tan, T. Chen, L. Gao, P. Kong, X. Zhang
Journal: HemaSphere (2022)

Background: Prognosis of refractory and relapsed acute myeloid leukemia (r/r AML) is challenge and no standard of treatment exists. Cladribine based regimen in treatment of r/r AML proved to be effective,while the total rate of response is limited. Aims: To explore whether the addition of liposomal adriamycin can improve the response. Methods: We registered a clinical trial, which is CLAG plus liposomal adriamycin (CLAG+PLD) regimen for re-induction of r/r AML (ChiCTR1800017569), to observe the response, overall survival (OS) and disease free suivival (DFS) of the patients. In addition to that, CLAG alone as salvage therapy (no PLD group) for RR-AML in our medical center were chosen as historical comparison Results: To observe the response, overall survival (OS) and disease free suivival (DFS) of the patients. In addition to that, CLAG alone as salvage therapy (no PLD group) for RR-AML in our medical center were chosen as historical comparison.Of the 55 patients who were evaluable for remission after CLAG +PLD treatment(PLD group), 27（49.1%）achieved CR and negative of MRD, 12（21.8%）achieved CR and positive of MRD, 5（9.1%）achieved partial response, and 11（20%）no response. In Contrast, no PLD group has inferior response rate,with the corresponding data is 24（46.6%）, 6（10.9%）,10（18.2%）,and 13（23.6%）respectively (p= 0.008).As for the 2-year OS and DFS, the median OS and DFS for PLD group has not reached and 10 months for noPLD group (p= 0.023 and p= 0.045 respectively). The safety observation did not find increasing toxicity in PLD group.In subgroup analysis of PLD group, the response between FLT3-ITD mutated group and wild group showed significant difference (p=0.006). Moreover, hematopoietic stem cell transplantation (HSCT) group exert superiority in both OS and DFS compared to no HSCT group with 2-year of follow-up（p＜0.0001 and p＜0.00001 respectively）. Image:Summary/Conclusion: In conclusion, CLAG + PLD is a prospective salvage regimen for r/r AML which brings improved response rates, 2-year OS and DFS and similar toxicities compared to CLAG.
circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop
Authors: Xiaomin Li, Jianjun Wang, Weihao Lin, Qinzi Yuan, Yanxia Lu, Haowei Wang, Yujia Chen, Lixia Chen, Peiling Dai, Huaicheng Long, Xuenong Li
Journal: Molecular Cancer (2022)

Abstract Background In recent years, an increasing number of studies have indicated that circular RNA plays crucial roles in regulating tumor development and chemoresistance. Using two high-throughput RNA sequence datasets, we previously found that circEXOC6B was downregulated in colon cancer. However, its role and mechanism in colorectal cancer (CRC) remained unknown. Methods Real-time quantitative PCR was used to examine the expression of circEXOC6B in CRC tissues. In vivo and in vitro functional experiments were performed to determine the suppressor role of circEXOC6B in CRC progression. RNA pull-down, mass spectrometry, RNA-binding protein immunoprecipitation, co-immunoprecipitation, fluorescence in situ hybridization, and immunofluorescence were applied to investigate the possible mechanisms connecting circEXOC6B to CRC growth and 5-fluorouracil-induced apoptosis. Chromatin immunoprecipitation, dual-luciferase assay, western blot, and immunohistochemistry were used to explore the mechanisms underlying the HIF1A regulation of RRAGB transcription. Results circEXOC6B was downregulated in CRC tissues, and its lower expression was associated with poor prognosis of patients. Functional experiments showed that circEXOC6B inhibited growth and increased the 5-fluorouracil-induced apoptosis of CRC cells in vitro and in vivo. Mechanistically, circEXOC6B inhibited the heterodimer formation of RRAGB by binding to it, thereby suppressing the mTORC1 pathway and HIF1A level. In addition, HIF1A upregulated the transcription of RRAGB by binding to its promoter region. Altogether, the results demonstrated that a HIF1A-RRAGB-mTORC1 positive feedback loop drives tumor progression in CRC, which could be interrupted by circEXOC6B. Conclusions circEXOC6B inhibits the progression of CRC and enhances the chemosensitivity of CRC cells to 5-fluorouracil by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop. circEXOC6B is a possible therapeutic target for CRC treatment.
P661: POPULATION-WIDE PATTERNS OF CARE IN CHRONIC LYMPHOCYTIC LEUKEMIA IN AUSTRALIA: AN ANALYSIS OF THE PHARMACEUTICAL BENEFITS SCHEME DATASET
Authors: C. Tam, F.-L. Zhao, R. Gauba, K. Yang, S. Azmi, S. C. Li
Journal: HemaSphere (2022)

Background: The treatment landscape in patients with chronic lymphocytic leukemia (CLL) is changing with the approvals of Bruton’s tyrosine kinase inhibitors (BTKis) in Australia. Aims: We sought to understand the practice impact of the introduction of publicly funded novel agents for the treatment of CLL. The objective of this study was to describe the evolving treatment patterns of Australian patients with CLL over the last 10 years using population-wide prescription records. Methods: Patients who initiated a treatment for CLL between 01/01/2011 and 07/31/2021 were extracted from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset. This dataset includes the dispensing records for 10% of the Australian population and captures all publicly funded treatments in Australia. The index date was defined as the commencement of any drug for the treatment of CLL. First-line (1L) therapy was defined as the first treatments prescribed for CLL. A patient was defined as relapsed/refractory (R/R) if they had commenced a drug which was in a different therapeutic category, or if they re-started the same regimen after a gap of more than 180 days. Descriptive analyses were conducted to examine the use of treatment regimens for the overall 10-year population by line of therapy. Analyses by calendar year were also performed to assess changes in treatment patterns. Results: Overall, 803 patients with CLL were identified. The majority of patients were male (65%) and age > 60 years (77%), with most being aged 70-79 years (33% of total). Many patients were receiving comedications at baseline, including antihypertensives (47%), antipsychotics or antidepressants (17%), and/or anticoagulants (13%). In the overall population (2011-2021), the majority of patients had received 1L treatment with fludarabine-cyclophosphamide-rituximab (FCR, 49%), chlorambucil ± CD20 (27%), or CD20 monotherapy (17%). The most commonly used regimens in R/R patients at any subsequent episode of treatment included CD20 monotherapy (56%), BTKi (41%) or FCR (33%). A trend in adoption of novel agents was observed throughout the years following their PBS listing. Analysis by calendar year showed that from 2011 to 2020 use of FCR in 1L decreased from 78% to 10%; and use of BTKis in R/R increased from 0% to 62%. Summary/Conclusion: CLL treatment patterns have significantly changed in Australia since the introduction of the BTKis (e.g., ibrutinib, acalabrutinib). The use of FCR in 1L CLL has decreased and use of BTKis in R/R patients has increased.
Small molecules as modulators of regulated cell death against ischemia/reperfusion injury
Authors: Dan‐Qian Chen, Yan Guo, Xin Li, Guo‐Qiang Zhang, Ping Li
Journal: Medicinal Research Reviews (2022)

Abstract Ischemia/reperfusion (IR) injury contributes to disability and mortality worldwide. Due to the complicated mechanisms and lack of proper therapeutic targets, few interventions are available that specifically target the pathogenesis of IR injury. Regulated cell death (RCD) of endothelial and parenchymal cells is recognized as the promising intervening target. Recent advances in IR injury suggest that small molecules exhibit beneficial effects on various RCD against IR injury, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis, and parthanatos. Here, we describe the mechanisms behind these novel promising therapeutic targets and explain the machinery powering the small molecules. These small molecules exert protection by targeting endothelial or parenchymal cells to alleviate IR injury. Therapies of the ideal combination of small molecules targeting multiple cell types have shown potent synergetic therapeutic effects, laying the foundation for novel strategies to attenuate IR injury.
P555: A PHASE 1B/2 STUDY OF THE CD123-TARGETING ANTIBODY-DRUG CONJUGATE PIVEKIMAB SUNIRINE (IMGN632) IN COMBINATION WITH VENETOCLAX (VEN) AND AZACITIDINE (AZA) FOR PATIENTS WITH CD123-POSITIVE AML
Authors: N. G. Daver, P. Montesinos, A. Aribi, G. Martinelli, J. Altman, G. Roboz, E. S. Wang, P. W. Burke, D. Jeyakumar, R. B. Walter, D. J. DeAngelo, H. P. Erba, A. Advani, L. Gastaud, X. Thomas, E. Todisco, N. Pemmaraju, L. Mendez, A. de la Fuente, G. Gaidano, A. Curti, N. Boissel, C. Recher, C. Schliemann, P. Vyas, C. M. Sloss, J. Wang, K. A. Malcolm, P. A. Zweidler-McKay, K. L. Sweet
Journal: HemaSphere (2022)

Background: Overexpression of CD123 occurs in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute lymphoblastic leukemia (ALL) and others. With limited expression on normal hematopoietic progenitor cells, the CD123 antigen is an attractive target for new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating cytotoxic payload of the IGN (indolinobenzodiazepine pseudodimer) class. In preclinical models of AML, IMGN632 exhibited potent anti-leukemia activity, with a wide therapeutic index. Confirming preclinical expectations, encouraging single-agent activity has emerged for IMGN632 in the ongoing Phase I trial in patients with CD123-positive BPDCN and AML (Daver. Blood (2019) 134 (Supplement_1):734.). Preclinical data have demonstrated increased activity with the addition of IMGN632 to AZA alone and to AZA+VEN in multiple AML xenograft and PDX models, leading to improved survival in these models (Kuruvilla. Blood (2019) 134 (Supplement_1):1375.). We have reported compelling activity (ORR 59% and CCR rate 38%) of the IMGN632 triplet in relapsed or refractory AML patients (Daver. ASH 2021 Abstract #372). The safety profile of the triplet included rates of cytopenias similar to those observed with AZA+VEN; additional low-grade adverse events included infusion-related reactions, dyspnea, fatigue, gastrointestinal toxicities, electrolyte imbalances, and pneumonia. Aims: This Phase 1b/2 study is designed to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with AZA and VEN to patients with relapsed and frontline CD123-positive AML. Methods: Dose escalation for the IMGN632+AZA+VEN triplet is complete. The Recommended Phase 2 Dose levels are: IMGN632 45 mcg/kg given on day 7 with 14 days of VEN, and either AZA 50 OR 75 mg/m2 for 7 days of a 28-day cycle. Results: N/A Summary/Conclusion: Phase 2 expansion cohorts for patients with untreated/frontline and relapsed AML are enrolling to further characterize the safety profile and assess the antileukemic activity. NCT04086264